Chronic Alcohol, Dementia, and CNS Fluid Homeostasis

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Project Summary/Abstract Alcohol use disorder (AUD) in mid-life is a significant, independent predictor of late-life dementia, particularly vascular cognitive impairment and dementia (VCID) that includes the common subtype cerebral amyloid angiopathy (CAA) characterized by deposits of amyloid-β (Aβ) in the cerebral vasculature. In only one decade, from 2005-2014, the rate of alcohol binging among the elderly rose 20% overall and by 50% in women only. The mechanisms underlying alcohol’s toxic effects on the central nervous system (CNS) remain incompletely understood, which limits the development of strategies targeted to reduce or prevent disease burden in heavy drinkers with and without CAA VCID. An underlying cause of alcohol’s damaging effects on the CNS is a poorly understood dysregulation of CNS fluid homeostasis. Preliminary evidence indicates that alcohol-associated abnormal fluid homeostasis manifests as enlarged cerebral ventricles and altered CSF flow dynamics. In humans, specifically, this manifests as lateral ventricular enlargement, and may reflect not only tissue loss but also itself be contributing to tissue damage and cognitive impairment. We propose that ethanol disrupts fundamentals of fluid homeostasis, by reducing CSF flow through the interconnected glymphatic and lymphatic systems, through biochemical and neuroimmune alterations thereby directly damaging the tissue. The functioning of glymphatic/lymphatic system supports fluid homeostasis and clears waste and toxins from the brain. Our proposed studies include a comprehensive series of experiments to quantitatively analyze alcohol’s effects on CSF secretion, glymphatic and lymphatic transport, and CSF/lymph ‘omics’ profiling in normal brain and with CAA VCID pathology. In Aim 1, we will determine how cEtoh interferes with CSF secretion in rats with/without VCID, using a novel MRI acquisition method to measure choroidal CSF secretion, as well as blood perfusion of the choroid plexus and cortex. We will also implement MRI sequences to measure brain morphometry in cEtoh-exposed rats with/without VCID and sample CSF, the meninges, and brain tissue to study pathology and biochemical lymphatic and inflammatory factors. In Aim 2, we will assess how cEtoh affects glymphatic-lymphatic transport, cerebral and meningeal lymphatic pathology, lymphatic waste output and cognition in rats with/without VCID. We will use dynamic contrast-enhanced MRI and computational fluid dynamics to measure CSF flow dynamics, glymphatic transport, and lymphatic waste drainage as affected by cEtoh and VCID, as well on CAA pathology and cognitive decline. In Aim 3 we will study how cEtoh compromises biochemical signaling and bio-physical changes in the CSF and lymph, including proteins that regulate fluid volume (renin-angiotensin) and proteins functioning in ion transport/signaling (Voltage dependent calcium signal, V-type proton ATPase and Carbonic Anhydrase). Molecular pathways that we identify can later be probed for therapeutic benefit.